Manufacture of water-soluble beta-hydroxynitriles

ABSTRACT

A process for making a water-soluble β-hydroxynitrile. A 1,2-epoxide and an inorganic cyanide salt are reacted in a solvent having aqueous methanol and a buffer therein to form βhydroxynitrile. The buffer substantially inhibits the formation of reaction products other than βhydroxynitrile. Optionally, water may be removed from the βhydroxynitrile by azeotropic distillation with acetonitrile and subsequently purified via vacuum distillation and filtration.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to processes for makingwater-soluble β-hydroxynitriles. The present invention more particularlyrelates to processes for making βhydroxynitriles from terminal1,2-epoxides and inorganic cyanides.

[0003] 2. Description of the Prior Art

[0004] β-hydroxynitriles may be prepared via ring-opening reactionsbetween epoxides and cyanides or cyanide equivalents. Methanol iscommonly employed as a solvent in ring-opening reactions of terminalepoxides because some cyanides, particularly potassium cyanide, aremoderately soluble therein. A problem, however, with the use of methanolis the possibility of side reactions forming undesirable by-products.Upon reaction of the terminal epoxide and potassium cyanide, a potassiumalkoxide of a β-hydroxynitrile is formed. The potassium alkoxide ishighly alkaline and, along with residual cyanides, renders the reactionproduct mixture very alkaline. The potassium alkoxide may then reactwith methanol to form potassium methoxide, which may then react with theepoxide to form a methyl ether, an undesirable by-product.

[0005] One means employed in the prior art to address the problem ofundesirable side reactions when using methanol as a solvent is to lowerthe alkalinity of the product mixture by implementing acidic reactionconditions. This, however, is problematic because acidic conditions mayresult in runaway or accelerated ring-opening reaction rates as well asin industrial hygiene and safety issues.

[0006] Another problem encountered is isolating water-solubleβ-hydroxynitriles from reaction product mixtures. Isolation ofnon-water-soluble β-hydroxynitriles has not presented problems sinceclassical extraction and chromatographic techniques can be employed.However, such classical extraction techniques are not useful withwater-soluble β-hydroxynitriles since they cannot be separated fromresidual cyanides or cyanide salts, which are also water-soluble.

[0007] Product color is another problem encountered during preparationof some water-soluble β-hydroxynitriles, particularly3-hydroxyvaleronitrile. When β-hydroxynitriles are prepared via aring-opening reaction from an epoxide and potassium cyanide, adark-colored refined oil is obtained upon distillation. To be suitablefor use, the dark distillate oil must be refined to further reduceimpurities, which results in a lighter color or substantially colorlessoil. Further refining of dark oil from conventional processes isdifficult via conventional distillation techniques.

[0008] It would be desirable to have an improved process for preparingβ-hydroxynitriles via ring-opening reactions between terminal1,2-epoxides and inorganic cyanides. It would further be desirable tohave a process whereby undesirable by-products are reduced oreliminated. It would further be desirable to have a process that enabledthe separation of water-soluble β-hydroxynitriles from cyanide salts andresidual cyanides. It would further yet be desirable to have a processfor preparing β-hydroxynitriles wherein resulting distillate oils arelighter in color, e.g., a pale yellow color in the instance of3-hydroxyvaleronitrile. It would further still be desirable to have aprocess for making β-hydroxynitriles that can easily be adapted todevelopment or commercial scale.

SUMMARY OF THE INVENTION

[0009] According to the present invention, there is a process for makinga water-soluble β-hydroxynitrile. The process comprises reacting a1,2-epoxide and an inorganic cyanide salt in an aqueous organic solventwith a buffer to form β-hydroxynitrile. The buffer at least partiallyinhibits the formation of reaction products other than β-hydroxynitrile.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0010] It was surprisingly found that a β-hydroxynitrile could beprepared via a ring-opening reaction between terminal 1,2-epoxides andinorganic cyanides while the incidence of undesirable by-products isreduced or eliminated. It was also surprisingly found that water-solubleβ-hydroxynitriles could be isolated from cyanide salts and residualcyanides. It was also surprisingly found that reaction product mixtureshaving 3-hydroxyvaleronitrile could be directly obtained with a lightercolor, i.e., a pale yellow, than reaction product mixtures obtained fromconventional processes.

[0011] In one embodiment, the present process employs a buffer thatsubstantially inhibits the formation of reaction products other than aβ-hydroxynitrile. The buffer is capable of protonating the alkoxidegenerated during the epoxide ring opening reaction and substantiallypreventing a side reaction between the alkoxide and methanol. The buffermust be acidic enough to protonate the alkoxide yet not be so acidic asto excessively accelerate the ring-opening reaction or create otherprocess control and/or hygiene problems. The buffer preferably has apK_(a) of between about 9.1 to about 13 and most preferably betweenabout 10 to about 12. Suitable buffers include inorganic buffers, suchas sodium bicarbonate or potassium bicarbonate, and organic buffers,such as phenol, succinimide, benzenesulfonamide, and combinationsthereof. A preferred buffer is sodium bicarbonate.

[0012] Optionally, the present process may employ azeotropicdistillation with acetonitrile to remove at least a portion of orsubstantially all the water from the product mixture having theβ-hydroxynitrile. To effect the distillation, acetonitrile is added,i.e., blended with the product mixture in a certain proportion to forman azeotropic mixture with the water in the product mixture. Therelative proportions of water and acetonitrile obtained during anazeotropic distillation will vary depending upon the composition of theproduct mixture, but will typically be between about 15 wt % to about 17wt % for water and between about 83 wt % to about 85 wt % at atmosphericpressure for acetonitrile. The azeotropic temperature of boiling ordistillation will typically range from between about 76° C. to about 82°C. at atmospheric pressure. Other useful azeotropes include toluene,acetone, and 2-butanone (methyl ethyl ketone).

[0013] Other conventional distillation processes may optionally beemployed in the present process to assist in the recovery of the productand to remove solvents, impurities, and by-products. Distillation may beemployed at atmospheric pressure, elevated pressure, or under reducedpressure or vacuum.

[0014] Further optionally, the present process may employ filtration tohelp purify the reaction mixture and/or product mixture. Filtration maybe employed one or more times between or after distillation runs toremove various inorganic salts that precipitate from thereaction/product mixtures. The inorganic salts are predominantlychemically related to the buffer. In a preferred process, a slightdeficiency of cyanide relative to epoxide is used, so there aretypically little, if any, salts chemically related to the cyanide salts.Any conventional filtration medium can be used, such as filter paper,cloth, and silica gel with or without anhydrous sodium sulfate. Thesilica gel and anhydrous sodium sulfate serve a dual function as afiltration medium and a desiccant. Filtration may be vacuum or pressureassisted or may be unassisted. After filtration, the filtration mediummay optionally be washed with a suitable solvent, such as methylenechloride, to ensure that substantially all of the product is collected.

[0015] The product takes the form of an oil. An advantage of the presentprocess is the ability to obtain product oils of high purity that arelight yellow or colorless depending upon the degree of purity desired.These are in contrast to the dark, heavy oils obtained when employingconventional processes.

[0016] In a preferred process, the reaction mixture is purified byemploying one or more azeotropic distillations to remove water, one ormore conventional distillations to remove methanol and 1, 2-epoxides,one or more filtrations between distillations to remove inorganic salts.The azeotropic distillation of the reaction mixture typically producesproduct oils of light yellow color. Conventional distillations may beused to render the oil colorless. Vacuum distillations, e.g. carried outat about 3 torr or less, especially high vacuum distillations, e.g.carried out at about 0.5 torr or less, are particularly useful inobtaining product of high purity. High vacuum distillations wherein theproduct itself is distilled, condensed, and collected are particularlyuseful.

[0017] The present process is useful in making a variety ofwater-soluble product β-hydroxynitriles. Suitable β-hydroxynitriles arethose corresponding to the product in the following reaction sequence:

[0018] wherein R¹ and R² are, independently, hydrogen or methyl, ethyl,n-propyl, i-propyl, t-butyl, phenyl, (CH₂)_(n)X, COR³, CO₂R³, orS(O)_(m)R³ groups; and wherein X is, independently, a phenyl, COR³,CO₂R³, S(O)_(m)R³,OR³, NR³R⁴ or N(O)R³R⁴ group; and wherein R³ and R⁴are, independently, hydrogen or a methyl, or ethyl group; and wherein nis, independently, 1 or 2 and m is, independently, 0, 1, 2, or 3.

[0019] The product β-hydroxynitriles may be racemic or enantiomericallyenriched or pure. Preferred product β-hydroxynitriles have structureswherein R¹ and R²are, independently, hydrogen or a methyl, ethyl,(CH₂)_(n)X, COR³, CO₂R³, or S(O)_(m)R³ group; X is, independently, aCOR³, CO₂R³, S(O)_(m)R³,OR³, NR³R⁴, or N(O)R³R⁴ group; R³ and R⁴ are,independently, hydrogen or a methyl group; n is 1; and m is,independently, 0, 1, 2, or 3. More preferred product β-hydroxynitrileshave structures wherein R¹ and R² are, independently, hydrogen or amethyl, ethyl, (CH₂)_(n)X group; X is, independently, a COR³, CO₂R³,S(O)_(m)R³,OR³, NR³R⁴ group; R³ and R⁴ are, independently, hydrogen or amethyl group; and n is 1; and m is, independently, 0, 1, 2, or 3. Mostpreferred product β-hydroxynitriles have structures wherein R¹ is ethyland R² is hydrogen.

[0020] Suitable product β-hydroxynitriles include, but are not limitedto, the following: racemic or chiral 3-hydroxyvaleronitrile(3-hydroxypentanenitrile) and racemic or chiral 3-hydroxybutanenitrile.A preferred β-hydroxynitrile is 3-hydroxyvaleronitrile. Chiral speciesof 3-hydroxyvaleronitrile are (R)-3-hydroxyvaleronitrile and(S)-3-hydroxyvaleronitrile.

[0021] The present process employs inorganic cyanides as reactants withβ-hydroxynitriles. Suitable inorganic cyanides include, but are notlimited to, the following: potassium cyanide, sodium cyanide, and coppercyanide. Potassium cyanide is preferred.

[0022] The present process is carried out in an aqueous organic solvent.Suitable aqueous organic solvents include, but are not limited to, thosecontaining methanol, ethanol, isopropanol, or ethers such astetrahydrofuran or dimethoxyethane. Water content should be at a levelsuch that the buffer and the epoxide and the cyanide are all at leastpartially soluble in the reaction mixture. Water content will typicallyrange from between about 10 volume percent (vol %) to about 90 vol %,and more preferably from between about 40 vol % to about 60 vol %, basedupon the total volume of the aqueous organic solvent.

EXAMPLES

[0023] Racemic 3-Hydroxyvaleronitrile and (R)-(+)-3-Hydroxyvaleronitrilewere prepared in accordance with the process of the present invention.

Example 1 Laboratory Synthesis of Racemic 3-Hydroxyvaleronitrile

[0024] A 1 liter (L) jacketed glass reaction vessel equipped with amechanical stirrer, temperature probe, addition funnel and a gas outletconnected to an aqueous sodium hydroxide scrubber was charged withpotassium cyanide (41.1 grams (g), 631 millimoles (mmol), 0.9equivalents (eq.)) and sodium bicarbonate (58.25 g, 693 mmol, 1.0 eq.).A recirculating bath was connected to a reactor jacket and set to 20° C.The reactor was then charged with 150 milliliters (mL) of methanol and150 mL of deionized water. The reaction mixture was agitated vigorouslyfor a period of about 30 minutes, and 1,2-epoxybutane (50.0 g, 693 mmol,1.0 eq.) was added to the reaction mixture via an addition funnel over aperiod of about 15 minutes while the reaction temperature was maintainedbetween 20-24° C. After the addition of 1,2-epoxybutane was complete,the temperature was gradually increased to about 28° C. over a period ofabout 15 minutes. The reaction mixture was then stirred overnight for aperiod of about 17 hours. The addition funnel was replaced with adistillation apparatus, and the batch was distilled at atmosphericpressure to remove most of the low boiling components, mainly methanol,from the reaction mixture. After most of the methanol had been distilled(head temperature=72° C.), the pot of the distillation apparatus wascharged while still hot with acetonitrile (1100 mL total, in portions of500 mL, 500 mL, and 100 mL) and the distillation was continued to removewater by means of an acetonitrile-water azeotrope. As the water wasdepleted from the reaction mixture, solids precipitated on the wall ofthe distillation vessel. The distillation was continued until the headtemperature reached 75° C. The product mixture in the distillation potwas cooled to 20° C. and held overnight. The product mixture contained5.6 wt % water by Karl-Fisher analysis. The product mixture was drainedfrom the distillation vessel as an oil. The precipitated solids wererinsed with acetonitrile (400 mL), the acetonitrile was removed byrotary evaporator, and the resulting oil was combined with the productmixture. The combined material was concentrated under vacuum to removevolatile materials, primarily acetonitrile, and then the oil wasdistilled under vacuum to afford the racemic 3-Hydroxyvaleronitrile(53.47 g, 539 mmol, 85% yield) as a colorless oil: boiling point (bp)90° C. -105° C. (2-3 torr); ¹H NMR (CDCl₃) δ 3.82 (m, 1H), 3.05 (s, 1H),2.5 (m, 2H), 1.59 (m, 2H), 0.95 (t, J=7 Hz, 3H). NMR is nuclear magneticresonance spectroscopy.

Example 2 Kilo Laboratory Synthesis of (R)-(+)-3-Hydroxyvaleronitrile

[0025] A 12L 4-necked round-bottomed flask equipped with a mechanicalstirrer, temperature probe, addition funnel, and a reflux condenser witha gas outlet connected to an aqueous sodium hydroxide scrubber wasemployed. The flask was charged with potassium cyanide (821 g, 12.61mol, 0.9 eq.), NaHCO₃ (1165 g, 13.87 mol, 1.0 eq.), methanol (3L), andwater (3L). There was a mild exotherm upon mixing as the temperaturerose from 20° C. to about 25° C. The reaction mixture was stirred for 30minutes as the temperature was brought to about 22° C. with a waterbath. (R)-(+)-1,2-epoxybutane (1000 g, 13.87 mol, 1.0 eq.) was thenadded to the reaction mixture in 100 mL increments over about 1.75 hourswhile the temperature was maintained between 18.0-22.6° C. withintermittent use of an ice-bath. The batch was allowed to stir atambient temperature for about 13 hours overnight. The batch temperaturethe following morning was 20.9° C. The reaction vessel was equipped witha distillation apparatus, and the reaction mixture was distilled atatmospheric pressure to remove most of the low boiling components,mostly methanol, from the reaction mixture. After most of the methanolhad been removed (head temperature=79° C.), the distillation pot wascharged while still hot with acetonitrile (18L total, in portions of2-4L) and the distillation was continued over the course of several daysto remove water by means of an acetonitrile-water azeotrope. As thewater was depleted from the reaction mixture, solids precipitated on thewall of the distillation vessel. The distillation was continued untilthe head temperature reached 78° C. The product mixture in thedistillation pot was cooled to 20° C. and held overnight. A 2L coarseglass frit was charged with 257 g of silica gel that was pre-conditionedwith acetonitrile. The product mixture was filtered through the silicagel. The precipitated solids were rinsed twice with acetonitrile (500mL), and the combined filtrates were concentrated under vacuum to removevolatile materials, primarily acetonitrile, to afford 1283 g of the(R)-(+)-3-Hydroxyvaleronitrile as a pale yellow oil. The oil wasdistilled under vacuum to afford the (R)-(+)-3-Hydroxyvaleronitrile of97 area percent purity by gas chromatography analysis overall purity and100% enantiomeric excess (1078 g, 539 mmol, 86% yield) as a colorlessoil: bp of 100° C.-105° C. (0.45 torr); ¹H NMR (CDCl₃) δ 3.82 (m, 1H),3.25 (s, 1H), 2.5 (m, 2H), 1.59 (m, 2H), 0.95 (t, J=7 Hz, 3H).

Example 3 Pilot Plant Synthesis of (R)-(+)-3-Hydroxyvaleronitrile

[0026] A 50-gallon nitrogen-purged glass-lined reactor with the jackettemperature set to 20° C. was charged with deionized water (45 kg),potassium cyanide (12.3 kg, 188.9 mol), sodium bicarbonate (17.5 kg,208.3 mol), and methanol (36.1 kg). The batch was agitated for about 30minutes then charged with (R)-(+)-1,2-epoxybutane (15 kg, 208.0 mol)over a period of about 6 hours while the temperature was maintainedbetween about 19-24° C. The batch was agitated overnight for about 12hours. The reactor was set for atmospheric distillation, and the batchwas distilled at atmospheric pressure until the batch temperature washigher than 85° C. The batch was cooled to 80° C., and acetonitrile(235.8 kg) was added in portions and the distillation was continued.After approximately half of the acetonitrile had been distilled, thebatch was cooled, filtered on an Aurora filtration device to removeaccumulated precipitated solids, and the filtrate was charged into thereactor. The distillation of acetonitrile was continued until the watercontent of the batch was <3 wt % by Karl-Fisher analysis, and the batchwas cooled. An Aurora filter was charged with dry silica gel (15.4 kg)and the silica gel was wetted with acetonitrile (24.7 kg). The excessacetonitrile was drawn off and sodium sulfate (3 kg) was carefullylayered onto the silica gel bed. The silica gel/sodium sulfatefiltration medium was covered with a filter cloth, and the batch wasfiltered through the silica gel/sodium sulfate filtration medium. Thebatch was charged back into the reactor, the reactor was set foratmospheric distillation, and the batch was distilled to the minimumstirrable volume to afford 22.0 kilograms (kg) of a solution of the(R)-(+)-3-Hydroxyvaleronitrile in acetonitrile. The solution was foundto contain 16.23 kg (86% yield) of (R)-(+)-3-Hydroxyvaleronitrile.

[0027] It should be understood that the foregoing description is onlyillustrative of the present invention. Various alternatives andmodifications can be devised by those skilled in the art withoutdeparting from the invention. Accordingly, the present invention isintended to embrace all such alternatives, modifications and variancesthat fall within the scope of the appended claims.

What is claimed is
 1. A process for making a water-solubleβ-hydroxynitrile, comprising: reacting a 1,2-epoxide and an inorganiccyanide salt in an aqueous organic solvent with a buffer to form areaction product having β-hydroxynitrile, said buffer at least partiallyinhibiting the formation of reaction products other than saidβ-hydroxynitrile.
 2. The process of claim 1, wherein said buffer has apK_(a) of between about 9.1 to about
 13. 3. The process of claim 2,wherein said buffer has a pK_(a) of between about 10 to about
 12. 4. Theprocess of claim 1, wherein said buffer is at least one selected fromthe group consisting of: sodium bicarbonate, potassium bicarbonate,phenol, succinimide, benzenesulfonamide, and combinations thereof. 5.The process of claim 4, wherein said buffer is sodium bicarbonate. 6.The process of claim 1, wherein said β-hydroxynitrile is selected fromthe group consisting of: 3-hydroxyvaleronitrile and3-hydroxybutanenitrile.
 7. The process of claim 6, wherein saidβ-hydroxynitrile is 3-25 hydroxyvaleronitrile.
 8. The process of claim1, wherein said 1,2-epoxide has the following structure:


9. The process of claim 8, wherein said 1,2-epoxide is 1,2-epoxybutane.10. The process of claim 1, wherein said inorganic cyanide salt isselected from the group consisting of: potassium cyanide, sodiumcyanide, and copper cyanide.
 11. The process of claim 10, wherein saidinorganic cyanide salt is potassium cyanide.
 12. The process of claim 1,wherein said inorganic cyanide salt is potassium cyanide, wherein said1,2-epoxide is 1,2-epoxybutane, wherein said β-hydroxynitrile is3-hydroxyvaleronitrile, and wherein said buffer is sodium bicarbonate.13. The process of claim 1, wherein said organic solvent is selectedfrom at least one of the group consisting of: methanol, ethanol,isopropanol, tetrahydrofuran, and dimethoxyethane.
 14. The process ofclaim 1, wherein said aqueous organic solvent is aqueous methanol. 15.The process of claim 1, wherein said aqueous organic solvent has a watercontent of between about 10 vol % to about 90 vol %, based on the totalvolume of said aqueous organic solvent.
 16. The process of claim 15,wherein said aqueous organic solvent has a water content range betweenabout 40 vol % to about 60 vol %, based on the total volume of saidaqueous organic solvent.
 17. The process of claim 1, further comprisingremoving at least a portion of said water resulting from said reactionproduct by azeotropic distillation with acetonitrile.
 18. The process ofclaim 17, wherein said azeotropic distillate comprises between about 15wt % to about 17 wt % water and between about 83 wt % to about 85 wt %acetonitrile when carried out at atmospheric pressure, and wherein saidazeotropic distillation is carried out at a temperature of between about76° C. to about 82° C., at atmospheric pressure.
 19. The process ofclaim 17, further comprising purifying said reaction product by vacuumdistillation and filtration.